Target-mediated exendin-4的药代动力学和药效学模型老鼠、猴子、和人类。

文章的细节

引用

复制到剪贴板

高W, Jusko WJ

Target-mediated exendin-4的药代动力学和药效学模型老鼠、猴子、和人类。

药物金属底座Dispos。2012年5月,40 (5):990 - 7。doi: 10.1124 / dmd.111.042291。Epub 2012年2月15日。

PubMed ID

22338110 (在PubMed

]

文摘

一个系统,即pharmacokinetic-pharmacodynamic (PK / PD)模型开发exendin-4占受体介导内吞作用通过glucagon-like肽受体1 (GLP-1R)作为其非线性处理的主要机制。时间的exendin-4浓度后静脉、皮下和连续静脉输注剂量在老鼠,静脉和皮下剂量在猴子身上,在人类进行静脉和皮下注入剂量。意味着数据挑战在exendin-4葡萄糖治疗后血糖和胰岛素在健康大鼠进行了分析。PK模型组件包括受体结合,随后的内化和退化,特异性的组织分布,并从等离子体线性一阶消除。吸收速率常数(k (a))在所有三个物种随剂量增加而降低。中央室的间隙(CL (c))(老鼠,3.62毫升/分钟;猴子,2.39毫升。分钟(1)。公斤(1);人类,1.48毫升。 min(-1) . kg(-1)) was similar to reported renal clearances. Selected PK parameters (CL(c), V(c), and k(off)) correlated allometrically with body weight. The equilibrium dissociation constant (K(D)) was within the reported range in rats (0.74 nM), whereas the value in monkeys (0.12 pM) was much lower than that in humans (1.38 nM). The effects of exendin-4 on the glucose-insulin system were described by a feedback model with a biphasic effect equation driven by free exendin-4 concentrations. Our generalized nonlinear PK/PD model for exendin-4 taking into account of drug binding to GLP-1R well described PK profiles after various routes of administration over a large range of doses in three species along with PD responses in healthy rats. The present model closely reflects underlying mechanisms of disposition and dynamics of exendin-4.

DrugBank数据引用了这篇文章

药物

Exenatide